Jul 2026· Annals of Neurology· 0 citations· 52 references
Medicine
TL;DR
In cognitively unimpaired older adults, elevated blood p-tau217 was linked to faster shrinkage in AD-specific brain regions, whereas NfL and GFAP were associated with more widespread atrophy, with NfL also associated with accelerated WMH accumulation.
Abstract
Objective
We aimed to investigate the associations between Alzheimer's disease (AD)-related blood biomarkers and changes in brain volumes and cerebrovascular burden in community-dwelling older adults.
Methods
We included 361 dementia-free participants with a Mini-Mental State Examination (MMSE) score ≥ 27 and without prior cerebrovascular events from a Swedish population-based study. Blood phosphorylated-tau217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured at baseline. Brain magnetic resonance imaging (MRI) was performed at baseline and after 3 and/or 6 years. Linear mixed models were used to examine associations between AD-related blood biomarkers and changes in volumes of total brain tissue (TBTV), lateral ventricles, hippocampus, amygdala, and white matter hyperintensities (WMHs).
Results
During the follow-up, higher p-tau217 was associated with faster volume loss in the hippocampus (β*year = -0.047, 95% confidence interval [CI] = -0.077 to -0.018) and in the amygdala (β*year = -0.064, 95% CI = -0.105 to -0.022). Elevated GFAP was linked to faster TBTV decline (β*year = -0.040, 95% CI = -0.059 to -0.021), ventricular enlargement (β*year = 0.028, 95% CI = 0.013 to 0.042), and hippocampal shrinkage (β*year = -0.038, 95% CI = -0.064 to -0.013). Participants with higher NfL showed steeper TBTV decline, ventricular enlargement, hippocampal and amygdala shrinkage, and faster WMH accumulation. Results remained largely consistent after excluding participants with mild cognitive impairment at baseline.
Interpretation
In cognitively unimpaired older adults, elevated blood p-tau217 was linked to faster shrinkage in AD-specific brain regions, whereas NfL and GFAP were associated with more widespread atrophy, with NfL also associated with accelerated WMH accumulation. These findings suggest that AD-related blood biomarkers may capture different dementia-related structural brain changes already at early stages. ANN NEUROL 2026.
A stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.
Keun You Kim, Hyunsun Ham, E. Yoon et al.· The journal of prevention of...· 0 citations
Serum NfL was associated with anatomically specific WM microstructural changes, with differing patterns across clinical groups, and no significant associations were observed between serum or CSF GFAP concentrations and diffusion tensor imaging metrics.
T. Magalhães, R. Casseb, A. Moraes et al.· Journal of Alzheimer's Disea...· 0 citations
Alzheimer’s disease (AD) and related dementias are a growing health and economic burden in India. Blood levels of amyloid beta (Ab), tau, and other proteins marking neuronal injury are biomarkers of AD risk and are potentially important for AD prevention.
In 2,224 participants from the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD), we performed gene-based analyses on (1) missense/loss-of-function (LoF) single-nucleotide variants (SNVs) and (2) brain-specific promoter/enhancer SNVs across 84 genes selected from AD GWAS and 25 gene-biomarker pairs selected from biomarker GWAS. We used variant-Set Test for Association using Annotation infoRmation (STAAR) across 7 neurodegenerative biomarkers measured in blood: Ab40, Ab42, Ab42/Ab40, total tau (tTau), tau phosphorylated at threonine 181 (pTau), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). We adjusted for age, sex, and genetic ancestry, with random intercepts for genetic relatedness and biomarker plate. Analyses incorporated weighted annotation scores (e.g., deleteriousness). Significant results (FDR-
q
< 0.1) were followed up with single variant analysis. Genes were also assessed for sex- and age-interactions using iSKAT.
Missense/LoF variants in 6 AD-associated genes (
ECHDC3
,
CLU
,
APOE
,
EPHA1
,
ICA1L
,
CASS4
) and 1 biomarker-associated gene (
APOE
) were associated with Ab40, Ab42/Ab40, pTau, and/or GFAP (FDR
q
< 0.1), with the most significant SNVs tending to be rare/low-frequency (MAF ≤ 0.05) and potentially deleterious. Promoter/enhancer variants in 1 AD-associated gene (
CCDC6
) were associated with Ab42/Ab40, with the index SNV being a potentially deleterious common variant (MAF = 0.27). Several associated variants appeared to have higher frequency in India compared to other global populations. Missense/LoF SNVs in two AD genes (
EPHA1
,
MS4A6A
) had sex-specific effects on Ab42 and/or tTau, and promoter/enhancer SNVs in four AD genes (
DGKQ
,
MS4A6A
,
MS4A4A
,
JAZF1
) had sex-specific effects on tTau and/or pTau. Missense variants in 12 AD genes and promoter/enhancer variants in two AD genes showed interaction with age on at least one biomarker, primarily GFAP and NfL with genetic effects tending to be stronger at older ages.
Rare and common variants in AD- and neurodegenerative biomarker-associated genes with increased frequency in India compared to other populations may impact blood levels of neurodegenerative biomarkers in South Asians.
Hasan Abu-Amara, Wei Zhao, Zheng Li et al.· Frontiers in Aging Neuroscie...· 0 citations
Structural brain changes during the earliest asymptomatic stages of Alzheimer’s disease (AD) remain poorly understood. Previous research in preclinical AD shows heterogeneous findings, reporting both subtle neuronal loss and paradoxical increases in grey matter (GM) volume. This study applies an extensive cerebrospinal fluid (CSF) biomarker panel to better understand the biological processes underlying longitudinal GM changes in cognitively unimpaired (CU) adults, spanning the amyloid/tau (AT) continuum.
We analysed data from 627 CU individuals from three longitudinal cohorts (ALFA+, Wisconsin ADRC, WRAP), with repeated MRI (3.5 ± 0.9 years) and baseline CSF biomarkers from the NeuroToolKit panel (Roche Diagnostics). Using non-negative matrix factorization, we decomposed the CSF biomarker levels into six latent components, reflecting amyloid-β (Aβ) pathology, tau-related pathophysiology with synaptic injury, neuroaxonal injury, microglial reactivity, astrocytic reactivity, and cytokine signalling. We tested associations between component weights and voxel-wise longitudinal GM volume changes using single-component and a joint-all components model. Analyses were performed across the full sample and stratified by AT status. Associations with longitudinal cognitive performance (PACC) were assessed using linear mixed-effects models.
The Aβ pathology component was the strongest and most widespread predictor of longitudinal GM atrophy, predominantly in temporal and frontal regions, also when controlling for tau pathophysiology, neuroaxonal injury, or neuroinflammatory components. Higher Aβ pathology scores were also associated with cognitive decline. The component capturing tau-related pathophysiology and synaptic injury initially associated with GM loss but lost significance after accounting for other biomarker components. In contrast, components reflecting microglial reactivity, astrocytic reactivity, and cytokine signalling were associated with longitudinal GM volume increases, with effects varying by AT stage.
In this large longitudinal sample of asymptomatic individuals, the Aβ-dominant biomarker component showed the strongest association with longitudinal GM atrophy and cognitive decline, beyond the effects of tau pathophysiology and neuroaxonal injury. While glial and inflammatory processes may contribute to transient GM increases in preclinical AD. A better understanding of these dynamic relationships between structural brain changes and various biological pathways at the earliest stages of AD is crucial to inform the development of interventions before irreversible neurodegeneration occurs.
W. Pelkmans, R. Cacciaglia, Michalis Kassinopoulos et al.· Molecular Neurodegeneration· 0 citations
Abstract INTRODUCTION Upstream neuroinflammation plays an important role in Alzheimer's disease (AD) but remains poorly understood. We tested whether two distinct neuroinflammatory markers are associated with cerebrovascular burden and amyloid beta (Aβ), and downstream, with plasma phosphorylated tau (p‐tau217), medial temporal lobe (MTL) cortical and hippocampal atrophy, and memory deficits. METHODS Cognitively unimpaired older adults without dementia or mild cognitive impairment were recruited from a community sample (Biomarker Exploration in Aging, Cognition, and Neurodegeneration; [BEACoN]; N = 126). We used structural equation modeling to test whether plasma chitinase‐3‐like protein 1 (YKL‐40) and glial fibrillary acidic protein (GFAP) contribute to distinct pathways. RESULTS Higher plasma YKL‐40 was associated with greater white matter hyperintensity (WMH), whereas higher plasma GFAP was related to increased 18F‐florbetapir (FBP) standardized uptake value ratio (SUVR). Higher plasma GFAP, WMH, and FBP SUVR were independently associated with increased p‐tau217. Plasma p‐tau217 was associated with reduced MTL cortical thickness and hippocampal volume. Reduced hippocampal volume was related to worse memory. DISCUSSION Future work can further investigate these neuroinflammatory pathways as potential therapeutic targets for AD.
Batool Rizvi, Jenna N. Adams, Alison R. Bamford et al.· Alzheimer's & Dementia· 1 citation
Abstract Introduction Chronic heart failure (HF) is associated with mild cognitive impairment (MCI), vascular dementia, and Alzheimer’s disease. Blood-based neurodegenerative biomarkers may support early risk stratification and outcome prediction in HF. Methods In the prospective Cognition.Matters-HF cohort study, serum neurofilament light chain (NfL), glial fibrillary acidic protein, and phosphorylated tau protein-181, as well as plasma amyloid-β peptides (Aβ38, Aβ40, Aβ42) and β-synuclein, were quantified longitudinally over 36 months using ultrasensitive immunoassays and immunoprecipitation mass spectrometry. Cerebral magnetic resonance imaging and standardized domain-specific cognitive testing were performed. Multivariable logistic regression was used to assess associations with future MCI, brain structural changes, and 5-year all-cause mortality. Results Among 104 patients with chronic HF (10% female, age 64 ± 10 years), all biomarkers except NfL increased significantly over 3 years (P < .05). Median annual percentage changes were 36.6% for phosphorylated tau protein-181, 4.6% for glial fibrillary acidic protein, 2.6% for β-synuclein, 0.6% for Aβ38, 0.5% for Aβ40, and 0.3% for Aβ42. After adjusting for clinical confounders, increases in Aβ38 and Aβ42 independently associated with future MCI, pathological white matter hyperintensity progression (>5% per year), and 5-year mortality (all P < .05). Glial fibrillary acidic protein levels and phosphorylated tau protein-181 trajectories were independently associated with pathological brain atrophy (>0.3% per year). Conclusion In clinically stable patients with chronic HF, longitudinal increases in circulating amyloid-β peptides associated with cognitive decline, structural brain changes, and mortality. Serial biomarker assessment provided stronger prognostic information than baseline measurements alone. Replication in larger cohorts is required.
J. Traub, Anna Frey, G. Homola et al.· ESC Heart Failure· 0 citations